Pharmacologic and Genetic Manipulations of Angiotensin Signaling in Thoracic Aortic Disease Models

Thoracic aortic aneurysms and dissections (TAAD) are a major cause of morbidity and mortality in patients. Many different risk factors have been associated TAAD, but hypertension is the largest risk factor. Subsets of TAAD patients have identifiable syndromic genetic diseases, yet a number of genetic non-syndromic patients have been identified. Infusion of angiotensin II into mouse models causes aortic disease through inflammation and fibrosis. An angiotensin type I receptor (AT1R) blocker (ARB) or an angiotensin converting enzyme (ACE) inhibitor (ACEi) can reverse aortic pathology in some mouse models. I set out to better understand the relationship between angiotensin and TAAD in our mouse models, and hypothesized that angiotensin II signaling through the AT1R contributes to thoracic aortic aneurysm formation in multiple model systems of disease, and that blocking related receptors in addition to the AT1R, such as the AT2R and Mas receptor, may have negative consequences. Previously identified genetic variants in the gene encoding smooth muscle alpha-actin, ACTA2, were modeled with Acta2-/- mice. I found that the ascending aorta and aortic root in these mice become significantly dilated over time. Acta2-/- mice are hypotensive, and increasing the blood pressure with a pharmaceutical and diet based regimen significantly accelerated and worsened the aortic phenotype. Treatment with losartan, an ARB, attenuated the aortic dilation, but captopril, an ACEi, did not decrease aortic growth and worsened the disease. Transverse aortic constriction (TAC) was used to study the ascending aorta and aortic root in response to increased biomechanical forces. Losartan attenuated the histologic and inflammatory changes associated with TAC, but captopril was again unable to rescue the phenotype. To understand why, I investigated other receptors blocked by ACEis: the angiotensin II type 2 receptor (AT2R) and the Mas receptor, a receptor for the Ang1-7 peptide. I found that cotreatment with captopril and an agonist for the AT2R had similar physiologic effects as the AT1R blocker despite being unable to prevent the fibrotic and inflammatory remodeling. In contrast, cotreatment with captopril and an agonist for the Mas receptor blocked remodeling but did not rescue aneurysm formation. My results, coupled with clinical data, indicate that fibrosis may be beneficial in the aorta, and show we must expand our understanding of the angiotensin system in aortic disease

PPAR action in insulin resistance unraveled by metabolomics: potential clinical implications

Metabolomic analysis will provide the next large set of clues to further our understanding of human health and disease. A recent study has elucidated the significant differences in the metabolomes of adipocytes, serum and an adipocyte cell line after activation of two nuclear receptors, peroxisome proliferator activated receptor β/δ (PPARβ/δ) and PPARγ. These findings hold great promise for explaining fundamental differences in the mechanisms of PPAR agonists and for identifying targets for the treatment of diabetes

On the mechanisms of late 20th century sea-surface temperature trends over the Antarctic Circumpolar Current

The Antarctic Circumpolar Current (ACC), with its associated three-dimensional circulation, plays an important role in global climate. This study concentrates on surface signatures of recent climate change in the ACC region and on mechanisms that contro

Characterization of Quantum Frequency Processors

Frequency-bin qubits possess unique synergies with wavelength-multiplexed lightwave communications, suggesting valuable opportunities for quantum networking with the existing fiber-optic infrastructure. Although the coherent manipulation of frequency-bin states requires highly controllable multi-spectral-mode interference, the quantum frequency processor (QFP) provides a scalable path for gate synthesis leveraging standard telecom components. Here we summarize the state of the art in experimental QFP characterization. Distinguishing between physically motivated ''open box'' approaches that treat the QFP as a multiport interferometer, and ''black box'' approaches that view the QFP as a general quantum operation, we highlight the assumptions and results of multiple techniques, including quantum process tomography of a tunable beamsplitter -- to our knowledge the first full process tomography of any frequency-bin operation. Our findings should inform future characterization efforts as the QFP increasingly moves beyond proof-of-principle tabletop demonstrations toward integrated devices and deployed quantum networking experiments

Characteristics of the sticky spot of Kamb Ice Stream, West Antarctica

Amplitude analysis of reflection seismic data reveals the presence of highly variable bed conditions under the main sticky spot and adjacent regions of the Kamb Ice Stream (KIS—formerly ice stream C). The sticky spot, which is a zone of bed that imparts high basal resistance to ice flow, is situated on a local topographic high composed of consolidated sediments or sedimentary rock. Any meltwater draining from upglacier along the base of the ice is routed around the sticky spot. The ice over the sticky spot includes, in at least some places, a seismically detectable basal layer containing a low concentration of debris, which locally thickens to 40 m over a topographic low in the bed. The ice-contact basal material ranges from dilated and highly porous to more-compacted and stiff, and perhaps locally frozen. The softer material is preferentially in topographic lows, but there is not a one-to-one correspondence between basal character and basal topography. We speculate that the 40-m-thick frozen-on debris layer formed by glaciohydraulic supercooling of lake-drainage events along a basal channel during the former, active phase of the ice stream. We also speculate that loss of lubricating water, perhaps from piracy upstream, contributed to the slowdown of the ice stream, with drag from the sticky spot playing an important role, and with the basal heterogeneity greatly increasing after the slowdown of the ice stream

Iron(III)-catalyzed chlorination of activated arenes

A general and regioselective method for the chlorination of activated arenes has been developed. The transformation uses iron(III) triflimide as a powerful Lewis acid for the activation of N-chlorosuccinimide and the subsequent chlorination of a wide range of anisole, aniline, acetanilide and phenol derivatives. The reaction was utilized for the late-stage mono- and di-chlorination of a range of target compounds such as the natural product nitrofungin, the antibacterial agent chloroxylenol and the herbicide chloroxynil. The facile nature of this transformation was demonstrated with the development of one-pot tandem iron-catalyzed dihalogenation processes allowing highly regioselective formation of different carbon-halogen bonds. The synthetic utility of the resulting dihalogenated aryl compounds as building blocks was established with the synthesis of natural products and pharmaceutically relevant targets

Generation and characterization of ultrabroadband polarization-frequency hyperentangled photons

We generate ultrabroadband photon pairs entangled in both polarization and frequency bins through an all-waveguided Sagnac source covering the entire optical C- and L-bands (1530--1625 nm). We perform comprehensive characterization of high-fidelity states in multiple dense wavelength-division multiplexed channels, achieving full tomography of effective four-qubit systems. Additionally, leveraging the inherent high dimensionality of frequency encoding and our electro-optic measurement approach, we demonstrate the scalability of our system to higher dimensions, reconstructing states in a 36-dimensional Hilbert space consisting of two polarization qubits and two frequency-bin qutrits. Our findings hold potential significance for quantum networking, particularly dense coding and entanglement distillation in wavelength-multiplexed quantum networks